Wajahat Z. Mehal, M.D., D.Phil.

Associate Professor
Section of Digestive Diseases and Immunobiology
more on this physician

Research Interests

Sterile Inflammation: Inflammation occurs in response to tissue injury even in the absence of signals from pathogens. There are numerous examples of this, from soft tissue swelling after trauma to the inflammatory infiltrate after a myocardial infarction. In the liver a number of clinically important conditions have a significant sterile inflammatory component. These include drug induced liver injury, alcoholic, and non-alcoholic liver disease. We have recently identified a two signals pathway consisting of activation of TLR9 by DNA from apoptotic self cells, and also activation of the inflammasome pathway. In addition we have found that the cheap and safe anti-inflammatory drug aspirin can inhibit the TLR9 mediated pathway. We are expanding these findings to test their general applicability to a wide range of liver diseases and also to further identify the role of up-stream activating steps including nuclear DNA, and metabolites of the uric acid pathway.

Liver Fibrosis: The hepatic stellate cell (HSC) is recognized as central to the development of liver fibrosis. We explored the paradigm that signals from dying cells result in HSC activation, and demonstrated that adenosine, which accumulates in conditions of tissue injury and inflammation, results in HSC activation. Interestingly in addition to up-regulating pro-fibrotic genes, adenosine also inhibits cytosolic calcium fluxes resulting in loss of HSC chemotaxis and contractility. We are currently examining other functional consequences of adenosine on HSC.

Liver Immunology: Antigens presented in the liver generate a suboptimal immune response often resulting in their chronic persistence (immune tolerance). This occurs clinically with tolerance to food antigens, to allo-antigens after transplantation, and to viral antigens during chronic infection with hepatitis viruses B and C. Despite these long-standing observations, it was recently realized that the healthy liver contains a large number of T cells (between 4-8 x 106 per gram of tissue). In this population conventional CD8+ T cells, and NK-T cells are over-represented, have an activated phenotype, and are undergoing cell cycle. We are interested in defining the interactions that occur between the healthy liver and the immune system during immune homeostasis, acute viral infections, and presentation of allo-antigens. We have shown that the healthy liver retains activated CD8+ T cells flowing through it. This retention is mediated mostly by hepatic ICAM-1 on Kupffer cells, and a proportion of the retained CD8+ T cells are undergoing apoptosis in the liver. Current work is focusing on the fate of activated CD8+ T cells when specific peptide is present in the liver, and also the ability of the liver to prime naive CD8+ T cells.

Figure Legend:
(A) Co-localization of activated CD8+ T cells (green) and Kupffer cells (red) in a mouse liver 30 min. after portal vein injection.

(B) Confocal microscopy of the mouse liver showing apoptosis of portal vein injected activated CD8+ T cells. CD8+ T cells were labeled with a non-specific membrane marker (CFSE: green) and a fluorochrome which signals mitochondrial membrane potential (Mito-tracker red). Viable cells are positive for CFSE and Mitotracker-red (both combine to give a yellow color) and apoptosing cells have lost the Mito-tracker signal and are only CFSE positive (green).

Selected Publications

• Mehal, WZ, and Crispe IN TCR ligation on CD8+ T cells creates double-negative cells in vivo. J. Immunol. 1998. 161: 1686-1693.
• Dao, T, Mehal, WZ, and Crispe, IN. IL-18 augments perforin-dependent cytotoxicity of liver NK-T cells. J. Immunol. 1999. 161: 2217-2222.
• Mehal, WZ, Juedes, AE, and Crispe, IN. Selective retention of activated CD8+ T cells by the normal liver. J. Immunol. 1999. 163: 3202-3210.
• Mehal, WZ. T cells in Primary Sclerosing Cholangitis and Autoimmune Hepatitis. In T Cells in the Liver. Editor: Crispe I.N.C. Wiley Publishers. 1999.
• Mehal, WZ, Azzaroli, F, and Crispe, IN. Antigen presentation by liver cells controls intrahepatic T cell trapping, whereas bone marrow-derived cells preferentially promote intrahepatic T cell apoptosis. J. Immunol. 2001. 167: 667-673.
• Mehal, WZ, Azzaroli, F, and Crispe, IN. Immunology of the healthy liver; old questions and new insights. Gastroenterology 2001. 120: 250-260.
• Lakhani SA, Masud1 A, Kuida K, Porter Jr GA, Booth CJ, Mehal WZ, Inayat I, Flavell RA. Caspases 3 and 7: Key Mediators of Mitochon Events of Apoptosis Science. 2006; 311(5762): 847-51.
• Kim SV, Mehal WZ, Dong X, Heinrich V, Pypaert M, Mellman I, Dembo M, Mooseker MS, Wu D, and Flavell RA. Modulation of Cell Adhesion and Motility in the Immune System by Myo1f. Science 6, 2006: 136-139
• Badu A, Jha MK, Matza D, Mehal WZ, Freichel M, Flockerzi V, Flavell RA. Critical role for the regulatory subunits of Cav channels in T lymphocyte function. PNAS. 103(42):15529-34, 2006.
• Qamar A, Sheikh SZ, Masud A, Jhandier MN, Inayat IB, Hakim W, Mehal W. In-vitro and In-vivo Protection of Stellate Cells From Apoptosis by Leptin. Digestive Diseases and Sciences. 51(10):1697-705, 2006.
• Hashmi A, Hakim H, Kruglov E, Watanabe A, Watkins W, Dranoff JA,. Mehal WZ. Adenosine inhibits cytosolic calcium signals and chemotaxis in hepatic stellate cells. American Journal of Physiology. 292(1):G395-401, 2007.
• Watanabe A, Hashmi A, Hakim W, Gomes D, Mehal WZ. DNA from Apoptotic Hepatocytes Induces HSC Differentiation and Inhibits Chemotaxis via TLR9. Hepatology. Hepatology 2007; 46(5):1509-18, 2007.
• Desrosiers MD, Cembrola KM, Fakir MJ, Stephens LA, Jama FM, Shameli A, Mehal WZ, Santamaria P, Shi Y. Adenosine deamination sustains dendritic cell activation in inflammation. J. of Immunology. 2007; 179(3):1884-92.
• Sohail M, Hashmi A, Hakim W, Watanabe A, Zipprich A, Groszmann R, , Dranoff J, Torok N, Mehal WZ. Adenosine Induces Loss of Actin Stress Fibers and Inhibits Contraction in Hepatic Stellate Cells via Rho Inhibition. Hepatology 2009;49:185-194.
• Hakim W, Sheikh S, Inayat I, Bia M, Caldwell C, Jain D, Smith D, Friedman A, Lorber M, Formica R, Mehal W. Pilot study of HCV Response in Patients with End Stage Renal Disease treated with Combination Pegylated Interferon ?-2a and Ribavirin. Nephrology Dialysis Transplantation In Press.
• Imaeda AB, Watanabe A, Sohail MA, Mahmood S, Mohamadnejad M, Sutterwala FS, Flavell RA, Mehal WZ. Acetaminophen Induced Hepatotoxicity is Dependent on TLR9 and the NALP3 Inflammasome. Journal of Clinical Investigation In Press

Contact

Campus Address
Department of Internal Medicine
333 Cedar Street (LMP 1080)
New Haven, CT 06520

E-mail
wajahat.mehal@yale.edu

Office Phone
(203) 785-3411